EP1274460A1 - Compose de promedicament aqueux comprenant une fraction de paclitaxel ou ses derives, procede de preparation dudit compose et composition pharmaceutique le contenant - Google Patents

Compose de promedicament aqueux comprenant une fraction de paclitaxel ou ses derives, procede de preparation dudit compose et composition pharmaceutique le contenant

Info

Publication number
EP1274460A1
EP1274460A1 EP01926177A EP01926177A EP1274460A1 EP 1274460 A1 EP1274460 A1 EP 1274460A1 EP 01926177 A EP01926177 A EP 01926177A EP 01926177 A EP01926177 A EP 01926177A EP 1274460 A1 EP1274460 A1 EP 1274460A1
Authority
EP
European Patent Office
Prior art keywords
formula
paclitaxel
compound
derivatives
water
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01926177A
Other languages
German (de)
English (en)
Other versions
EP1274460A4 (fr
Inventor
Byung-Wook Jo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kolon Life Science Inc
Original Assignee
Kolon Industries Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kolon Industries Inc filed Critical Kolon Industries Inc
Publication of EP1274460A1 publication Critical patent/EP1274460A1/fr
Publication of EP1274460A4 publication Critical patent/EP1274460A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a water-soluble prodrug compound comprising a moiety of paclitaxel or derivatives thereof, a method of preparing the same, and a pharmaceutical composition comprising the same. More particularly, the present invention relates to a water-soluble prodrug compound comprising a moiety of paclitaxel or derivatives thereof, exhibiting good bioavailability and reduced side effect by dissolving aids, and a method of preparing the same and a pharmaceutical composition comprising the same.
  • Paclitaxel (known as taxol) is a compound originally isolated from the bark of the Pacific Yew tree, and a derivative thereof (e.g. docetaxel) is semi-synthetically produced from baccatin III derivatives from the bark of the Pacific Yew tree. These paclitaxel or derivatives thereof has a diterpene structure of formula ⁇ .
  • paclitaxel has been used as an anticancer agent manufactured by Bristol-Myers Squibb Company USA in
  • paclitaxel prohibits mitotic cancer cell division rather than the conventional anticancer agent, it has relatively low toxic to body and strong anticancer ability and it was widely used in the 1990's.
  • This paclitaxel has been approved by the U.S. Food and Drug Administration (FDA) to treat ovarian cancer in 1992, breast cancer in 1994 and Kaposi's sarcoma.
  • FDA U.S. Food and Drug Administration
  • paclitaxel is used for treating liver cancer, lung cancer, articula rheumacute, Alzheimer's disease, and a clinical testing of paclitaxel with various drugs have been conducted which is expected to increase the use of paclitaxel.
  • Paclitaxel is insoluble in water, and it is administrated with surfactants such as Cremophor-EI (polyoxyethylated castor oil), or polysorbate.
  • surfactants such as Cremophor-EI (polyoxyethylated castor oil), or polysorbate.
  • taxol parenteral fluid (Taxol, Birtsol-Myers Squibb) clinically applied used 6 mg of paclitaxel and 527 mg Cremophor-EI as a surfactant in 1 ml of 49.7 % (v/v) alcohol solution
  • taxotere parenteral fluid (Rhone-Poulenc Rorer) using docetaxel
  • paclitaxel derivatives includes 20 mg of docetaxel and 0.5 ml of polysorbate 80 as a surfactant in 1.83 mml of 13 % (w/w) alcohol solution.
  • paclitaxel produces side effects such as neuropathy, myopathy, myalgia, neutropenis and docetaxel (taxotere) produces unfavorable side effects such as stomatitis, edema and malaise.
  • the conventional paclitaxel prodrug has a long half life time (T 1 2 ) in which paclitaxel prodrug is hydrolyzed to generate to paclitaxel, of 1 to 8 hours in rat plasma, the half-life time should be reduced about 10 minutes or less.
  • the object of the present invention is to provide a water-soluble prodrug compound including a moiety of paclitaxel or derivatives thereof, which is rapidly hydrolyzed in vivo so that it exhibits improved bioavailability.
  • Another object of the present invention is to provide a water-soluble prodrug compound including a moiety of paclitaxel or derivatives thereof, which has substantially no side effect caused by dissolving aids.
  • Still another object of the present invention is to provide a pharmaceutical composition including the water-soluble prodrug compound.
  • a water-soluble prodrug compound including a moiety of paclitaxel or derivatives thereof, represented by formula 1.
  • XC (CH 2 ) m CX CHOCO-D D represents a moiety of paclitaxel or derivatives thereof
  • M is an integer of 1 to 6
  • n is an integer of 10 to 1 ,000
  • X represents O, S or NH
  • R 1 represents H or CH 3 )
  • the present invention further provides a method of preparing the water-soluble prodrug compound including a moiety of paclitaxel or derivatives thereof, represented by formula 1 in which a compound of formula 2 reacts with a polyethylene glycol derivatives compound.
  • O-D D represents a moiety of paclitaxel or derivatives thereof
  • m is an integer 1 to 6
  • n is an integer of 10 to 1 ,000
  • X represents O, S or NH
  • R' represents H or CH 3
  • Y is a suitable leaving group such as halogen.
  • the compound of formula 2 is prepared by esterifying paclitaxel or derivatives thereof and a compound of formula 4, or prepared by reacting paclitaxel or derivatives thereof with a silyl agent to prepare a compound of formula 5, reacting the compound of formula 5 with a compound of formula 4 to prepare a compound of formula 6, and deprotecting the compound of formula 6 with a weak acid.
  • R 2 is CH 3 CO or H
  • Pt is a silyl protecting group
  • D' is a moiety of the compound of formula 5
  • R' is H or CH 3 .
  • Y is a suitable leaving group such as halogen.
  • the present invention provides a pharmaceutical composition including a water-soluble prodrug compound with a moiety of paclitaxel or derivatives thereof, of formula 1 as an active ingredient.
  • FIG. 1 is a graph showing hydrolysis results according to time of 2'-monomethoxy poly ethylene glycol
  • FIG. 2 is a linear graph showing hydrolysis results according to time of 2'-monomethoxy poly ethylene glycol
  • FIG. 3 is a graph showing hydrolysis result according to time of 7-monomethoxy poly ethylene glycol
  • FIG. 4 is a linear graph showing hydrolysis result of 7-monomethoxy poly ethylene glycol 5000-succinyloxymethyloxycarbonyl-paclitaxel according to Example 6 in 37 ° C rat plasma.
  • the present invention relates a water-soluble prodrug compound including paclitaxel or derivatives thereof.
  • the water-soluble prodrug compound of the present invention is obtained by introducing a new self-immolating linker which is spontaneously decomposed, into paclitaxel and water-soluble polymer and combining water-soluble polymer with the resulting product, and the prodrug compound is rapidly hydrolyzed by an esterase to generate physiologically active paclitaxel.
  • the water-soluble prodrug compound is represented by formula 1. ⁇ Formula 1 >
  • R is formulas a or b, ⁇ Formula a>
  • D represents a moiety of paclitaxel or derivatives thereof, for example, moiety of docetaxel, m is an integer of 1 to 6, preferably 1 to 3, n is an integer of 10 to 1 ,000, preferably 10 to 460, more preferably 40 to 230,
  • the prodrug compound of formula 1 is prepared by reacting a compound of formula 2 with polyethylene glycol compound derivatives of formula 3 in the presence of a solvent such as benzene, toluene or chlorobenzene.
  • the amount of the polyethylene glycol compound derivatives is suitably 1 to 3 equivalents based on 1 equivalent of the compound of formula 2.
  • the amount of polyethylene glycol compound is less than 1 equivalent, the reaction does not complete, whereas the amount thereof is more than 3 equivalents, the unwanted side reaction occurs.
  • reaction-accelerating catalyst may be iodine or potassium iodide, and the amount thereof is suitably 1 to 5 equivalents based on 1 equivalent of the compound of formula 2.
  • the base may be sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, or potassium hydroxide, and the amount thereof is suitably 1 to 5 equivalents based on 1 equivalent of the compound of formula 2.
  • the cation capture may be crown ethers such as 18-crown-6 ether, and the amount thereof is suitably 0.3 to 5 equivalents based on 1 equivalent of the compound of formula 2.
  • R, D, m, n, X and R' have the meanings given above, and Y is a suitable leaving group such as halogen.
  • the compound of formula 2 may be prepared by esterifying paclitaxel or derivatives thereof with a compound with carbonyl group of formula 4 in the presence of a solvent such as methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, tetrahydrofuran or ethyl ether.
  • a solvent such as methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, tetrahydrofuran or ethyl ether.
  • the compound with carbonyl group is desirably 1 to 3 equivalents based on 1 equivalent of paclitaxel or derivatives thereof. If the amount of the compound with carbonyl group is less than 1 equivalent, the reaction does not complete, whereas the amount thereof is more than 3 equivalents, the unwanted side reaction occurs.
  • This reaction is performed in the presence of a base such as N,N-diisopropylethylamine, triethylamine or pyridine.
  • a base such as N,N-diisopropylethylamine, triethylamine or pyridine.
  • the amount of the base is desirably 1 to 3 equivalents based on 1 equivalent of paclitaxel or derivatives thereof.
  • the reaction occur at 2'-OH of paclitaxel or derivatives thereof.
  • compound of formula 2 may be accomplished by the following procedure. Paclitaxel or derivatives thereof reacts with a silyl agent in a solvent such as dichloromethane to prepare a compound of formula 5.
  • a silyl group in the silyl agent protects a 2'-OH group of paclitaxel or derivatives thereof, and the silyl agent may be t-butyl dimethyl silyl chloride, trimethyl silyl chloride, trimethyl silyl cyanide, hexa methyl disilazine or trimethylsilyl diethyl amine.
  • the amount of silyl agent is desirably 1 to 3 equivalents based on 1 equivalent of paclitaxel or derivatives thereof.
  • This reaction may be performed by adding paclitaxel or derivatives thereof to a solvent and simultaneously adding a silyl agent, a base and a soluble-aid to a solution of paclitaxel or derivatives thereof.
  • a base is dissolved in a soluble-aid to prepare a base solution and then base solution and a silyl agent are added to a solution of paclitaxel or derivatives thereof.
  • the exemplary of the base may be imidaz ⁇ le, and the soluble-aid may be a silyl agent solution in a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.
  • the compound of formula 5 esterification-reacts with the compound with carbonyl group of formula 4 in the presence of a solvent such as dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride, tetrahydrdofuran or ethyl ether to obtain a compound of formula 6.
  • a solvent such as dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride, tetrahydrdofuran or ethyl ether
  • N,N-diisopropy!ethylamine, triethylamine or pyridine may be further added. In this reaction, the reaction occur a 7-OH group.
  • the compound of formula 6 deprotects with a weak acid such as HF, citric acid, acetic acid, polystyrene formic acid, formic acid, or tetraammonium fluoride in the presence of a solvent such as acetonitrile, methanol, tetrahydrofuran or diethylether, to prepare a compound of formula 2.
  • the weak acid is a solution with a concentration of 0.1 to 10% and a solvent may be acetonitrile, methanol or tetrahydrofuran.
  • R 1 is C 6 H 6 or (CH 3 ) 3 CO
  • Pt is a silyl protecting group
  • D' is moiety of the compound of formula 5
  • Y is a suitable leaving group such as halogen.
  • the prodrug compound of the present invention is hydrolyzed by an esterase in vivo to convert paclitaxel as an active ingredient.
  • a new self-immolating linker which is spontaneously decomposed, decreases a steric hindrance of paclitaxel during the approach of the esterase so that the prodrug compound is rapidly hydrolyzed and the spontaneous decomposition of the self-immolating linker is rapidly spontaneously decomposed and the conversion from the prodrug to paclitaxel promptly occur.
  • polyethylene glycol derivatives used for preparing the prodrug compound of the present invention polyethyleneglycol has a linear or branched neutral polymer and various molecular weights, and it has no toxic to human and is safety material which is approved as internally used by FDA. Accordingly, polyethylene glycol group gives water-solubility to the prodrug compound paclitaxel.
  • the prodrug of the present invention has advantages that it has no side effect such as neouropathy. myopathy, myalgia, neutropenia, stomatitis, edema or malaise caused by surfactants and organic solvents used in the conventional prodrug compound (Taxol, Taxotere).
  • the prodrug compound of the present invention may be useful as active ingredients in pharmaceutical composition for treating breast, ovarian and lung cancers, and Kaposi's sarcoma, and for treating liver cancer, stomach cancer, rheumacute articular, or Alzheimer's disease.
  • the pharmaceutical composition including the prodrug compound as active ingredients of the present invention may further include pharmaceutically acceptable additives.
  • Paclitaxel (1.0 g, 1.171 mmol) was dissolved in 10 mi of anhydrous methylenechloride.
  • Diisopropylethylamine (307.6 ⁇ l, 1.76 mmol) was added to the resulting solution and the mixture was cooled to 0 ° C in a ice bath.
  • Chloromethyl chloroformate (167.3 ⁇ l, 1.76 mmol) was slowly added to the resulting mixture and reacted for 2 hours at 0 ° C.
  • the resulting reaction solution was dried under reduced pressure in a rotary vacuum dryer and the residue is recrystalized from ethylacetate/n-hexane to yield 900 mg of a product (81%).
  • Monomethoxypolyethyleneglycol 20000-succinate (11.1g, 1.1 mmole), sodium iodide (472.mg, 3.149mmole), potassium carbonate (261 mg, 1.888mmole), and 18-crown-6 ether (396.5mg, 1. ⁇ mmole) were added to the resulting solution and refluxed for 20 hours.
  • the resulting mixture was cooled to room temperature and filtered to remove inorganic material followed by the drying of filtrate under reduced pressure.
  • the resulting material was recrystallized from methylenechloride/ether. The recrystallized material was purified with high performance liquid chromatography for collection (Prep.
  • the resulting material was filtered to remove un-dissolved material.
  • the organic layer was washed twice with water and the separated organic layer was dried over anhydrous magnesium sulfate to remove water and dried under reduced pressure followed by the recrystallization of the dried material from isopropyl alcohol to obtain a solid material.
  • the solid material was purified with high performance liquid chromatography for collection (Prep. HPLC) to obtain 9.2 g of pure product (72%).
  • the prodrug compounds according to Examples 2, 6 to 12 were added and dissolved in 1 ml of distilled water followed by the measurement of haze with a Hazemeter (NHD-300A, Nippon denshoku IND.) according to the increase in the amount of the prodrug compound.
  • the solubility was defined by the amount of the prodrug compound at which the fluidity occurs and the haze is 0.5 or less than. The results are presented in Table 1.
  • the prodrug compounds of Examples 2, 6 to 12 had water-solubility of 400mg or more and exhibited improved water-solubility.
  • 10ml of rat plasma was precisely balanced in a 37 ° C water bath and the prodrug compounds of Examples 2 and 6 were added in the water bath and dissolved (the amount of paclitaxel included in the prodrug compound was corresponded to O. ⁇ mg).
  • 100 ⁇ l of each the solution was withdrawn from the solution and admixed to a 200 ⁇ l of acetonitrile-included tub, and centrifuged at 11 ,000 rpm for ⁇ minutes followed 200 ⁇ l of the obtained supemantant was analyzed with a high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the concentration of the prodrug and paclitaxel in the sample were measured after which the results are shown in Figs. 1 and 3, respectively.
  • the linear graphs showing these results are presented in Figs. 2 and 4, respectively.
  • at least ⁇ O % of the prodrug compound of Examples 2 and 6 was converted to paclitaxel within about 2 minutes and 100% thereof was converted to paclitaxel within 10 minutes.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un composé de promédicament aqueux comprenant du paclitaxel ou ses dérivés. Ce composé de promédicament présente une biocapacité améliorée.
EP01926177A 2000-04-15 2001-04-13 Compose de promedicament aqueux comprenant une fraction de paclitaxel ou ses derives, procede de preparation dudit compose et composition pharmaceutique le contenant Withdrawn EP1274460A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
KR20000019873 2000-04-15
KR2000019873 2000-04-15
PCT/KR2001/000618 WO2001078784A1 (fr) 2000-04-15 2001-04-13 Compose de promedicament aqueux comprenant une fraction de paclitaxel ou ses derives, procede de preparation dudit compose et composition pharmaceutique le contenant

Publications (2)

Publication Number Publication Date
EP1274460A1 true EP1274460A1 (fr) 2003-01-15
EP1274460A4 EP1274460A4 (fr) 2005-06-29

Family

ID=19664577

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01926177A Withdrawn EP1274460A4 (fr) 2000-04-15 2001-04-13 Compose de promedicament aqueux comprenant une fraction de paclitaxel ou ses derives, procede de preparation dudit compose et composition pharmaceutique le contenant

Country Status (6)

Country Link
US (1) US6703417B2 (fr)
EP (1) EP1274460A4 (fr)
JP (1) JP3538606B2 (fr)
KR (1) KR100406739B1 (fr)
AU (1) AU2001252711A1 (fr)
WO (1) WO2001078784A1 (fr)

Families Citing this family (10)

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Publication number Priority date Publication date Assignee Title
KR20030049023A (ko) * 2001-12-13 2003-06-25 주식회사 코오롱 방사선 감작제용 파클리탁셀 유도체
KR20030068955A (ko) * 2002-02-19 2003-08-25 주식회사 코오롱 새로운 중간 결합체(ｓｅｌｆ-ｉｍｍｏｌａｔｉｎｇｌｉｎｋｅｒ) 화합물과 그 제조방법, 이를 이용한파클리탁셀 또는 이의 유도체의 잔기를 포함하는 수용성프로드럭 화합물, 그의 제조방법 및 이를 유효성분으로포함하는 약제 조성물
KR20080106254A (ko) * 2006-03-28 2008-12-04 니폰 가야꾸 가부시끼가이샤 탁산류의 고분자 결합체
CN101534861B (zh) * 2006-09-15 2013-10-02 安佐制药股份有限公司 具有基于位阻酯的生物可降解连接基的聚环氧烷
JP2010503707A (ja) * 2006-09-15 2010-02-04 エンゾン ファーマスーティカルズ インコーポレイテッド オリゴヌクレオチドの送達を目的としたヒンダードエステル系生体分解性リンカー
EP2199281A1 (fr) * 2008-12-19 2010-06-23 DSM IP Assets B.V. Acides thioiques en tant que bloc de construction de polythioesters
PL388144A1 (pl) * 2009-05-29 2010-12-06 Przedsiębiorstwo Produkcyjno-Wdrożeniowe Ifotam Spółka Z Ograniczoną Odpowiedzialnością Solwaty (2R,3S)-3-tert-butoksykarbonylamino-2-hydroksy-3-fenylopropionianu 4-acetoksy-2α-benzoiloksy -5β,20-epoksy-1,7β,10β-trihydroksy-9-okso-taks-11-en-13α-ylu, sposób ich otrzymywania i zastosowanie
JP2014514300A (ja) * 2011-04-08 2014-06-19 スファエラ ファーマ ピーティーイー リミテッド 置換メチルホルミル試薬並びに化合物の物理化学的性質及び／又は薬物動態学的性質を改質するためのそれらの使用方法
DK2925718T3 (en) 2012-11-30 2018-10-22 Novomedix Llc SUBSTITUTED BIARYL SULPHONAMIDS AND USE THEREOF
CN116332881B (zh) * 2023-05-30 2023-08-08 大连理工常熟研究院有限公司 一种硫酯衍生物的制备方法

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WO2001019407A2 (fr) * 1999-09-13 2001-03-22 Nobex Corporation Promedicaments a base de taxane
WO2001019406A2 (fr) * 1999-09-13 2001-03-22 Nobex Corporation Promedicaments amphiphiles

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WO2000064486A2 (fr) * 1999-04-28 2000-11-02 Vectramed, Inc. Conjugues de medicaments polymeres actives par voie enzymatique
WO2001019407A2 (fr) * 1999-09-13 2001-03-22 Nobex Corporation Promedicaments a base de taxane
WO2001019406A2 (fr) * 1999-09-13 2001-03-22 Nobex Corporation Promedicaments amphiphiles

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See also references of WO0178784A1 *

Also Published As

Publication number Publication date
AU2001252711A1 (en) 2001-10-30
US20030050333A1 (en) 2003-03-13
WO2001078784A1 (fr) 2001-10-25
EP1274460A4 (fr) 2005-06-29
JP3538606B2 (ja) 2004-06-14
KR20010100902A (ko) 2001-11-14
JP2003531130A (ja) 2003-10-21
US6703417B2 (en) 2004-03-09
KR100406739B1 (ko) 2003-11-20

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